Several theories of addiction posit that dependent smoking results from an imbalance in reward processing, such that cigarettes and smoking related stimuli become "overvalued" and/or other non-smoking reinforcers are "undervalued". Yet among chronic smokers, substantial individual variability has been observed in the neural and behavioral responses to both smoking and non-smoking stimuli. Thus, individual differences in reward processing-either present at baseline or resulting from chronic nicotine exposure-might be an important factor contributing to vulnerability to nicotine dependence and relapse. Dopamine is a key neurotransmitter involved in reward processing, and there is growing evidence that polymorphisms related to dopamine receptor function impact processing of both nicotine and non-drug reinforcers. The purpose of this application is to utilize established human laboratory procedures and functional neuroimaging to rigorously assess the impact of DRD2/ANKK1 Taq IA and DRD4 VNTR polymorphisms on the processing of both smoking and non-smoking rewards, and ultimately, the ability to achieve abstinence when given an incentive to do so. The specific aims are: 1) To determine whether the DRD2/ANKK Taq IA and DRD4 VNTR polymorphisms predict neural response to smoking and non-smoking reward in smokers;2) To determine whether these same polymorphisms predict behavioral response to smoking and non-smoking reward in smokers;3) To determine whether these polymorphisms predict the ability to refrain from smoking when given a monetary incentive for abstinence. 4) To determine whether the relationship between these polymorphisms and the ability to achieve abstinence in an incentive-based test is mediated by responsiveness to smoking and non-smoking reward in smokers. In the proposed study, we will recruit participants (N=80) based on genotype in a 2 x 2 between subjects design. Half the participants will be comprised of individuals who are carriers for the A1 allele of the TaqIA variant and half will be comprised of individuals who are carriers for the 7R (7 repeat) allele of the DRD4 VNTR. We predict that abstinent smokers who are carriers of the A1 allele of the TaqIA polymorphism will demonstrate reduced Blood Oxygenation Level-Dependent (BOLD) response to non- smoking rewards in reward-related areas as well as reduced behavioral responsiveness to non-smoking reward, while carriers of the 7R allele of the DRD4 VNTR will demonstrate potentiated BOLD response to smoking rewards and hypersensitivity to the behavioral effects of smoking rewards. We further predict that individuals carrying the A1 allele of the Taq IA polymorphism or a 7R allele of the DRD4 VNTR will be less able to refrain from smoking during an experimental model of relapse in which abstinence is reinforced with money. Finally, we predict that this effect will be mediated by the more proximal endophenotypes related reward sensitivity. These findings would help to elucidate important pathways by which polymorphisms related to the D2 and D4 receptors might confer risk for smoking and relapse. PUBLIC HEALTH RELEVANCE: Nicotine use and dependence is associated with an imbalance in reward processing in which smoking is "overvalued" and non-smoking alternatives are "undervalued." These changes do not manifest equally in all smokers. One possible source of variance is genetics;polymorphisms related to dopamine receptor function are related to both cue-induced craving and to sensitivity to non-smoking rewards. The experiment proposed here will explore the relationship between genetic variants related to the D2 and D4 dopamine receptors, the neurobiological and behavioral responsiveness to both smoking and non-smoking rewards, and the ability to refrain from smoking when given a monetary incentive to do so.